The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Role of Tyrosine Kinase in Desflurane-induced Preconditioning

Background: Short administration of volatile anesthetics preconditions myocardium and protects the heart against the consequences of subsequent ischemia. Activation of tyrosine kinase is implicated in ischemic preconditioning. The authors investigated whether desflurane-induced preconditioning depends on activation of tyrosine kinase.

Methods: Sixty-four rabbits were instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size (IS). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits underwent a treatment period consisting of either no intervention for 35 min (control group, n = 12) or 15 min of 1 minimum alveolar concentration desflurane inhalation followed by a 10-min washout period (desflurane group, n = 12). Four additional groups received the tyrosine kinase inhibitor genistein (5 mg/kg) or lavendustin A (1.3 mg/kg) at the beginning of the treatment period with (desflurane-genistein group, n = 11; desflurane-lavendustin A group, n = 12) or without desflurane inhalation (genistein group, n = 9; lavendustin A group, n = 8).

Results: Hemodynamic values were similar in all groups during baseline (left ventricular pressure, 87 +/- 14 mmHg [mean +/- SD]; cardiac output, 198 +/- 47 ml/min), during coronary artery occlusion (left ventricular pressure, 78 +/- 12 mmHg; cardiac output, 173 +/- 39 ml/min), and after 2 h of reperfusion (left ventricular pressure, 59 +/- 17; cardiac output, 154 +/- 43 ml/min). IS in the control group was 55 +/- 10% of the area at risk. The tyrosine inhibitors had no effect on IS (genistein group, 56 +/- 13%; lavendustin A group, 49 +/- 13%; each P = 1.0 vs. control group). Desflurane preconditioning reduced IS to 40 +/- 15% (P = 0.04 vs. control group). Tyrosine kinase inhibitor administration had no effect on IS reduction (desflurane-genistein group, 44 +/- 13%; desflurane-lavendustin A group, 44 +/- 16%; each P = 1.0 vs. desflurane group).     

Stimulation of choline/Mg2+ antiport in rat erythrocytes by mefloquine.

In non Mg(2+)-loaded and non malaria-infected rat erythrocytes, mefloquine (100 micromol x l (-1)) stimulated choline/Mg2+ antiport without affecting the Na+/Mg2+ antiport. The stimulation of the choline/Mg2+ antiport by mefloquine, found in this study, and by trifluoperazine and fluvoxamine, reported previously [Ebel et al. Biochim Biophys Acta 2004; 1167: 132-40], was associated with CF3 groups attached to the quinoline or benzene ring. The effect of mefloquine on choline/Mg2+ antiport in vitro was not related to the antimalarial action of mefloquine in vivo. In rat erythrocytes, the choline/Mg2+ antiport can be differentiated from the Na+/Mg2+ antiport through the use of cinchonine that inhibited the choline/Mg2+ antiport [Ebel et al. Biochim Biophys Acta 2002; 1559: 135-44], and mefloquine that stimulated the choline/Mg2+ antiport, whereby the Na+/Mg2+ antiport was not affected by either drug at proper concentrations. The Na+/Mg2+ antiport and choline/Mg2+ antiports behave as different molecular entities.     

Distribution of cholinergic neurons in the chick spinal cord during embryonic development. Comparison of ChAT immunocytochemistry with AChE histochemistry.

The location of cholinergic neurons was studied during the development of the chick embryo spinal cord. A comparison between choline acetyltransferase (ChAT) immunocytochemistry and acetylcholinesterase (AChE) histochemistry was performed. ChAT-positive neurons could be detected only from embryonic day 9 (E9) onwards by the FITC technique and from E12 onwards by the PAP technique. These neurons were located mainly in the medial and lateral motor columns in the ventral horn of the gray matter and some of them were observed in the intermediate region of the spinal cord. AChE-containing cell bodies were much more numerous than the ChAT immunoreactive ones and were distributed in the ventral horn of the gray matter, the intermediate gray region and mostly off the apical part of the dorsal horn. ChAT should provide a reliable and specific marker for cholinergic neurons.     

Accelerated 3D echo-planar spectroscopic imaging at 4 Tesla using modified blipped phase-encoding.

Whole-brain echo-planar spectroscopic imaging (EPSI) often substantially lengthens MRI/MRSI (magnetic resonance spectroscopic imaging) protocols. To halve acquisition time, application of a blipped phase-encoding (PE) gradient during the EPSI readout (RO) was previously suggested by PE of the even RO echoes in k-space at an interstitial location along k(PE), separated from the odd RO echoes, effectively reducing the number of PEs by a factor of 2. However, the approach is very susceptible to phase inconsistencies between even and odd RO echoes in the presence of B(0) inhomogeneities and gradient imbalance, leading to ghosting in the PE direction. In this work, the blipped PE gradient is placed in between pairs of even/odd RO gradient lobes to avoid these problems. This approach is demonstrated in a phantom and in normal human brain in vivo at 4T. While the proposed method allows substantial reduction in metabolite ghosting, it may be limited by the presence of a relatively large spurious signal at the Nyquist frequency.     

Impaired visual perceptual categorization in right brain-damaged patients: failure to replicate.

The association of both Perceptual Categorization (PC) and Semantic Categorization (SC) with sensory performance was investigated. 28 RBD, 27 LBD and 21 non-brain-damaged subjects were tested with the PC and SC tasks described by Warrington and Taylor (1978) and with 6 sensory tasks. PC was related to sensory performance in RBD but not in LBD patients. SC was only marginally associated with sensory ability in both lesion groups. RBD and LBD patients differed significantly at neither PC nor at SC. Thus the dissociation between PC and SC, described by Warrington and Taylor (1978) was not replicated. Moreover, PC and SC were significantly correlated in both RBD and LBD patients. This suggests that the serial organization of PC and SC is questionable. It is concluded that the associations we obtained between SC, PC and sensory performance are likely to be functional. The contribution of a cognitive factor ("abstraction") to PC and SC is discussed.     

Patient and partner perceptions about preventing genital herpes transmission

Research over the past decade has provided a new understanding of genital herpes transmission and measures that can reduce transmission risk. It is unclear, however, how those affected by genital herpes access and interpret this information to make decisions about risk behaviours. This study measured how people with genital herpes and their partners perceived prevention methods, barriers and facilitating factors, and information sources. Formative evaluation was conducted, and survey data were collected from visitors to four websites (n=1849). Results suggest that the prevention messages of refraining from sex during disease outbreaks and condom use have had the greatest reach. Misconceptions about the potential role of suppressive antiviral therapy for genital herpes prevention persist among a substantial percentage of respondents. Accurate information concerning transmission between outbreaks, the effectiveness of condoms and the role of antiviral medication is critical in preventing the spread of genital herpes.     

Signal transduction via both human low-affinity IgG Fc receptors, Fc gamma RIIa and Fc gamma RIIIb, depends on the activity of different families of intracellular kinases

In contrast to IgG Fc receptor II (Fc gamma RIIa), the function of Src-family kinases, Syk and phosphoinositide 3-kinase (PI3K) in signal transduction of glycosylphosphatidylinositol-anchored Fc gamma RIIIb has not been analyzed in detail. Therefore pharmacological inhibitors were used to define the role of specific kinases in signalling of Fc gamma RIIa and Fc gamma RIIIb in myeloid cells. We demonstrate that the broad tyrosine kinase inhibitor genistein, the Src-family kinase inhibitor PP2, and the Syk kinase inhibitor piceatannol inhibit [Ca2+]i rise induced by both low-affinity Fc gamma R in neutrophils. Genistein and PP2 additionally prevent Fc gamma R-triggered hydrogen peroxide generation. In contrast, wortmannin, a PI3K inhibitor, which blocks Fc gamma RIIIb activation completely, abolishes Fc gamma RIIa-mediated [Ca2+]i flux only in the beginning. In addition, herbimycin A, a further specific inhibitor of Src-family kinases leads to a delayed Fc gamma RIIa-induced [Ca2+]i rise in THP-1 cells. In summary, our data demonstrate differences between both low-affinity IgG Fc receptors, and provide evidence for an essential role of Src-family kinases, Syk and PI3K in Fc gamma RIIIb-mediated signalling.     

Culex restuans (Diptera: Culicidae) relative abundance and vector competence for West Nile Virus

The abundance and vector competence of Culex restuans Theobald and Culex pipiens L. were compared to determine the relative importance of these species as West Nile virus (WNV) vectors in the northeastern United States. Abundance was estimated from egg raft collections at 12 sites in Albany, Suffolk, and Richmond counties, New York, during July, August, and September 2002 and 2003. Cx. restuans was more abundant than Cx. pipiens in both urban and rural areas, comprising 86% of 1,623 egg rafts collected. Vector competence for WNV was estimated after feeding on an artificial bloodmeal and in vitro transmission assays. The vector competence of the two species for WNV was similar, but the dynamics of infection seems to be mosquito species dependent. These findings suggest an important role for Cx. restuans in WNV transmission cycles in New York.